Process for the preparation of imidazobenzodiazepines

ABSTRACT

A multistep process is presented for the preparation of imidazobenzodiazepines of the formula ##STR1## wherein X is selected from the group consisting of hydrogen, halogen, nitro and trifluoromethyl; Y is selected from the group consisting of hydrogen, halogen or trifluoromethyl; R 1  is hydrogen or lower alkyl and R 2  is a disubstituted amine 
     Also presented are novel intermediates utilized in the process. 
     The end products and intermediates are useful as sedatives, anxiolytics, muscle relaxants and anticonvulsants. 
     The end products are especially useful in intravenous compositions for use in preoperative anesthesia.

This is a division of application Ser. No. 043,417, filed May 29, 1979.

DESCRIPTION OF THE INVENTION

The present invention relates to a process to produceimidazobenzodiazepines of the formula ##STR2## wherein X is selectedfrom the group consisting of hydrogen, halogen, nitro andtrifluoromethyl; Y is selected from the group consisting of hydrogen,halogen or trifluoromethyl; R₁ is hydrogen or lower alkyl and R₂ is adisubstituted amine

The imidazobenzodiazepines are useful as sedatives, anxiolytics, musclerelaxants and anticonvulsants, a description of these compounds can befound in Belgian Pat. No. 839,364 which is incorporated herein byreference.

As utilized in the present specification, the terms "halo" or "halogen"mean all four forms thereof, i.e., chlorine, bromine, iodine andfluorine, except where otherwise indicated.

As used in this disclosure, the term "lower alkyl" or "alkyl"comprehends both straight and branched chain (C₁ to C₇) carbon-hydroxyradicals, prefereably C₁ to C₄ carbon-hydroxy radicals, such as, methyl,ethyl, propyl, isopropyl, butyl and the like.

By the term "disubstituted amino" is meant a nitrogen atom substitutedby lower alkyl or aralkyl, e.g., benzyl. Also within the ambit of theterm "disubstituted amino" is a cyclic moiety wherein the dialkylsubstituents are combined with the nitrogen atom and another heteroatom,e.g., oxygen to form a cyclic group, e.g., morpholino.

The following reaction scheme sets forth the novel process. ##STR3##wherein X is selected from the group consisting of hydrogen, halogen,nitro and trifluoromethyl; Y is selected from the group consisting ofhydrogen, halogen or trifluoromethyl; R₁ is hydrogen or lower alkyl, R₂is a disubstituted amine and R₃ is an amino or substituted amino R₄ islower alkyl or hydrogen.

I→II

The nitromethylene compound of formula I is a known compound. Methodsfor its preparation are described in the previously mentioned BelgianPat. No. 839,364. This starting material is thereafter reacted with anitrosating agent, such as, nitrosyl chloride or nitrous acid which isgenerated from sodium or potassium nitrate in an acetic acid solvent. Asa solvent, acetic acid is preferred but mixtures of acetic acid and a C₁to C₄ alcohol or water may also be utilized. The reaction temperaturemay range from about 0° C. to 50° C. with about room temperature aspreferred.

II→III

The compound of formula II is thereafter alkylated by reaction with adiazoalkane, such as, diazomethane or diazoethane in a wide range ofsolvents, such as, inert hydrocarbons or chlorinated hydrocarbons, e.g.,benzene, toluene, chloroform and methylene chloride or ethers, such as,tetrahydrofuran. The temperature of the reaction may range from about-50° C. to +50° C. with about room temperature as preferred.

III→IV or II→IV

The compounds of formulas III or II may thereafter undergo anucleophilic displacement of the nitro group with an amine nucleophile.Suitable nucleophiles include ammonia, primary and secondary amines oralkali metal salts of primary and secondary amines. Examples of theabove include monoalkylamines such as monomethylamine andmonoethylamine, dialkylamines such as diethylamine, aromatic primary andsecondary amines such as aniline and monomethyl-aniline, cyclic aminessuch as morpholine, piperidine and pyrrolidone, functionalizedderivatives of the above amines such as 2-hydroxyethylamine(ethanolamine), 2-aminoethylamine (ethylenediamine),carbalkoxymethylamine, glycine esters.

A variety of solvents may be utilized, such as, inert hydrocarbons orchlorinated hydrocarbons, e.g., benzene toluene, chloroform or methylenechloride or ethers, such as, tetrahydrofuran. An excess of theparticular amine chosen is utilized in the reaction. The reactiontemperature may range from about 0° C. to 100° C. with room temperatureas preferred.

IV→V

The compound of formula IV is thereafter reduced by reaction with sodiumborohydride. A variety of solvents may be utilized, such as, C₁ -C₄alcohols or mixtures with inert hydrocarbons or chlorinatedhydrocarbons, e.g., benzene, toluene, chloroform or methylene chloride,ethers or dimethylformamide. Preferred is a mixture of ethanol andtetrahydrofuran. The reaction temperature varies from about 0° C. to 50°C. with room temperature as preferred.

V→VI

The compound of formula V where R₃ is amino, dialkylamine or a cyclicamine may be cyclized to the desired imidazobenzodiazepines of formulaVI by condensation with an aliphatic or aromatic aldehyde, e.g.,acetaldehyde, in the presence of an acid catalyst, such as, p-toluenesulfonic acid or hydrochloric or sulfuric acid. Suitable solventsinclude C₁ to C₄ alcohols, inert hydrocarbons and chlorinatedhydrocarbons as mentioned earlier, high boiling ethers, acetic acid andpropronic acid. The reaction temperature may vary from about roomtemperature to 120° C. with the boiling point of the chosen solvent aspreferred.

The compounds of formulas II, III, IV and V are novel intermediates inthe present process and also exhibit activity as sedatives andanxiolytics.

EXAMPLE 17-Chloro-5-(2-fluorophenyl)-N-methoxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine

A solution of diazomethane in ether was added to a suspension of 6 g(0.0163 mole) of7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methaniminein 100 ml of tetrahydrofuran. After sitting at room temperature for 1 hrin excess diazomethane was destroyed by addition of glacial acetic acid.The solvent was evaporated under reduced pressure and the residue waspassed over 100 g of silica gel using methylene chloride.Crystallization from ether/hexane gave light yellow crystals with mp130°-133° C.

EXAMPLE 27-Chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepine-2-N'-hydroxycarboximidamide

A mixture of 7.2 g (0.02 mole) of7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methanimineand 50 ml of ethanol containing 20% (v/v) of ammonia was allowed to sitat room temperature overnight. The precipitated crystals were collected,washed with methanol, 2-propanol and ether to leave end product. Theanalytical sample was recrystallized from tetrahydrofuran/ethanol togive yellowish crystals with mp 248°-249° C.

EXAMPLE 37-Chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepine-2-N'-hydroxycarboximidamide4-oxide

A mixture of 1 g (2.65 mmole) of7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine4-oxide and 20 ml of methanol containing 20% (v/v) of ammonia wasallowed to sit overnight. The precipitated crystals were collected,washed with methanol, water and methanol to yield end product with mp252°-254° C. dec. For analysis it was recrystallized frommethanol/ethanol/tetrahydrofuran to give yellow crystals with mp258°-260° C.

EXAMPLE 47-Chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepine-2-N'-hydroxy-N-methylcarboximidamide

A solution of 3.6 g (0.01 mole) of7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methaniminein 50 ml ethanol containing 20% (v/v) of methylamine was allowed to sitat room temperature overnight. The solvents were evaporated underreduced pressure and the residue was partitioned between methylenechloride and water. The organic phase was dried and evaporated and theresidue was crystallized from ether to give yellowish crystals. Theanalytical sample was recrystallized from methylene chloride/ethylacetate/hexane, mp 223°-225° C. dec.

EXAMPLE 57-Chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepine-2-N'-hydroxy-N,N-dimethylcarboximidamide

Reaction of7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine,7.2 g (0.02 mole), with dimethylamine in tetrahydrofuran yielded productwhich was recrystallized from methanol/ethyl acetate for analysis, mp160°-164° C.

EXAMPLE 67-Chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepine-2-N'-hydroxy-N,N-dimethylcarboximidamide4-oxide

A solution of dimethylamine in tetrahydrofuran, 50 ml, (20%, v/v) wasadded to a suspension of 7.5 g (0.02 mole) of7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methaniminein 50 ml of tetrahydrofuran. After sitting at room temperatureovernight, the mixture was evaporated under reduced pressure and theresidue was partitioned between methylene chloride and saturated aqueoussodium bicarbonate solution. The organic phase was dried and evaporatedand the residue was crystallized from ethyl acetate to yield end productas crystals. The analytical sample was recrystallized frommethanol/ethyl acetate, mp 190°-192° C. dec.

EXAMPLE 7[7-Chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepin-2-yl](4-methyl-1-piperazinyl)methanoneoxime

This compound was obtained by reacting7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methaniminewith N-methylpiperazine in tetrahydrofuran. The analytical sample wasrecrystallized from ethanol, mp 198°-200° C.

EXAMPLE 8[7-Chloro-5-(2-fluorophenyl)-4-oxide-3H-1,4-benzodiazepin-2-yl](4-methyl-1-piperazinyl)methanoneoxime

Reaction of7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methaniminewith N-methylpiperazine in tetrahydrofuran gave this compound as yellowcrystals. For analysis it was recrystallized from ethanol, mp 184°-186°C. dec.

EXAMPLE 97-Chloro-5-(2-fluorophenyl)-2-[1-[(hydroxyimino)methyl]pyrrolidinyl]-3H-1,4-benzodiazepine

Reaction of7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methaniminewith pyrrolidine in tetrahydrofuran overnight at room temperatureyielded yellowish crystals. For analysis a sample was recyrstallizedfrom tetrahydrofuran/ethanol, mp 175°-178° C.

EXAMPLE 107-Chloro-5-(2-fluorophenyl)-2-[1-[(hydroxyimino)methyl]pyrrolidinyl]-3H-1,4-benzodiazepine4-oxide

This compound was obtained by reacting7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methanonewith pyrrolidine in tetrahydrofuran. The product was crystallized fromethyl acetate/ether and recrystallized for analysis from methanol/ethylacetate, mp 168°-172° C.

EXAMPLE 117-Chloro-5-(2-fluorophenyl)-2-[4-[(hydroxyimino)methyl]morpholinyl]-3H-1,4-benzodiazepine

Morpholine, 5 ml, was added to a suspension of 5 g of7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methaniminein 75 ml of tetrahydrofuran. After standing at room temperature for 6hours the reaction mixture was filtered and the filtrate was evaporated.The residue was partitioned between methylene chloride and sodiumbicarbonate solution. The organic phase was dried and evaporated and theresidue was crystallized from ether to yield end product as yellowcrystals. The analytical sample was recrystallized from methanol/ethylacetate, mp 191°-193° C. dec.

EXAMPLE 127-Chloro-5-(2-fluorophenyl)-2-[4-[(hydroxyimino)methyl]morpholinyl]-3H-1,4-benzodiazepine4-oxide

Reaction of7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methaniminewith a solution of morpholine in tetrahydrofuran gave similarly7-chloro-5-(2-fluorophenyl)-2-[4-[(hydroxyimino)methyl]morpholinyl]-3H-1,4-benzodiazepine4-oxide. It was crystallized from ethyl acetate and recrystallized foranalysis from a mixture of methanol/tetrahydrofuran/ethyl acetate togive yellow crystals with mp 211°-213° C. dec.

EXAMPLE 137-Chloro-5-(2-fluorophenyl)-N'-methoxy-3H-1,4-benzodiazepine-2-carboximidamide

A mixture of 1.5 g (0.004 mole) of7-chloro-5-(2-fluorophenyl)-N-methoxy-α-nitro-3H-1,4-benzodiazepine-2-methanimineand 20 ml of methanol containing 20% (v/v) of ammonia was allowed to sitat room temperature for 41/2 hours. After partial evaporation theresidue was partitioned between methylene chloride and saturated aqueoussodium bicarbonate solution. The methylene chloride layer was dried andevaporated. The residue was passed over neutral alumina using ether.Crystallization of the combined eluates from ether/hexane gave endproduct as colorless crystals with mp 120°-124° C.

EXAMPLE 147-Chloro-5-(2-fluorophenyl)-N-methyl-N'-methoxy-3H-1,4-benzodiazepine-2-carboximidamide

Reaction of 0.5 g of7-chloro-5-(2-fluorophenyl)-N-methoxy-α-nitro-3H-1,4-benzodiazepine-2-methaniminewith methylamine in ethanol (20% v/v) gave the same workup andpurification procedure colorless product, crystallized fromether/hexane; mp 140°-142° C.

EXAMPLE 157-Chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-N'-hydroxy-carboximidamide

7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepine-2-N'-hydroxycarboximidamide,5 g or 0.015 mole, was dissolved by warming in a mixture of 250 ml ofethanol and 100 ml of tetrahydrofuran. Sodium borohydride, 2 g (0.053mole) was added at room temperature and the mixture was stirredovernight. The solvents were evaporated partially under reduced pressureand the residue was partitioned between methylene chloride and saturatedaqueous sodium bicarbonate solution. The organic phase was dried andevaporated and the residue was crystallized from ethyl acetate to yieldyellowish product. The analytical sample was recrystallized from ethylacetate/hexane, mp 216°-218° C.

EXAMPLE 167-Chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-N'-hydroxy-N-methylcarboximidamide

Reduction of 3.45 g (0.01 mole) of7-chloro-5-(2-fluorophenyl)-3H-1,4-benzazepine-2-N'-hydroxy-N-methylcarboximidamidewith 1 g (0.026 mole) of sodium borohydride in 100 ml of ethanol for 4hours at room temperature gave, after the workup described above, endproduct, crystallized from ethyl acetate. The analytical sample wasrecrystallized from methanol/ethyl acetate, mp 215°-217° C. dec.

EXAMPLE 177-Chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-N'-hydroxy-N,N-dimethylcarboximidamide

This compound was similarly obtained by treatment of7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepine-2-N'-hydroxy-N,N-dimethylcarboximidamidein ethanol/tetrahydrofuran with sodium borohydride for 4 hours at roomtemperature. The usual workup and crystallization from ether gave endproduct. For analysis it was recrystallized from methanol/ethyl acetate,mp 178°-180° C.

EXAMPLE 187-Chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-4-oxide-2-N'-hydroxy-N,N-dimethylcarboximidamide

Reduction of7-chloro-5-(2-fluorophenyl)-3H-1,4-benzodiazepine-2-N'-hydroxy-N,N-dimethylcarboximidamide4-oxide with sodium borohydride in ethanol for 3 hours at roomtemperature gave the end compound. For analysis it was recrystallizedfrom ethyl acetate/ether, mp 145°-150° C. dec. (solvate with 1/6 mole ofether).

EXAMPLE 197-Chloro-5-(2-fluorophenyl)-2,3-dihydro-N-hydroxy-α-(1-pyrrolidinyl)-1H-1,4-benzodiazepine-2-methanimine

This compound was similarly obtained by reduction of7-chloro-5-(2-fluorophenyl)-2-[1-[(hydroxyimino)methyl]pyrrolidinyl]-3H-1,4-benzodiazepinewith sodium borohydride in ethanol/tetrahydrofuran. It was crystallizedfrom ethanol/ether and recrystallized from tetrahydrofuran/ethanol togive off-white crystals with mp 200°-202° C. dec.

EXAMPLE 207-Chloro-5-(2-fluorophenyl)-2,3-dihydro-N-hydroxy-α-(1-pyrrolidinyl)-1H-1,4-benzodiazepine-2-methanimine4-oxide

Reduction of 2 g (5 mmole) of7-chloro-5-(2-fluorophenyl)-2-[1-[(hydroxyimino)methyl]pyrrolidinyl]-3H-1,4-benzodiazepine4-oxide with 0.8 g sodium borohydride in 50 ml of ethanol and 25 ml oftetrahydrofuran (4 hours at room temperature) gave after the usualworkup and crystallization from ethyl acetate the end product. Foranalysis it was recrystallized from methanol/ethyl acetate, mp 182°-183°C. dec.

EXAMPLE 217-Chloro-5-(2-fluorophenyl)-2,3-dihydro-N-hydroxy-α-(4-morpholinyl)-1H-1,4-benzodiazepine-2-methanimine

This compound was obtained by reduction of7-chloro-5-(2-fluorophenyl)-2-[4-[(hydroxyimino)methyl]morpholinyl]-3H-1,4-benzodiazepinewith sodium borohydride in ethanol/tetrahydrofuran (4 hours at roomtemperature). It was crystallized from ether and recrystallized frommethanol/ethyl acetate/hexane for analysis to give off-white needleswith mp 133°-137° C.

EXAMPLE 227-Chloro-5-(2-fluorophenyl)-2,3-dihydro-N-hydroxy-α-(4-morpholinyl)-1H-1,4-benzodiazepine-2-methanimine4-oxide

Analogously, reduction of7-chloro-5-(2-fluorophenyl)-2-[4-[(hydroxyimino)methyl]morpholinyl]-3H-1,4-benzodiazepine4-oxide gave the end compound. It was crystallized from ethyl acetateand recrystallized from methanol/ethyl acetate for analysis to leavelight yellow crystals with mp 192°-193° C. dec.

EXAMPLE 238-Chloro-3-dimethylamino-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine

A mixture of 1.8 g (5 mmole) of7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-N'-hydroxy-N,N-dimethylcarboximidamide,0.5 g (16.6 mmole) of paraformaldehydr, 0.1 g of p-toluene sulfonic acidhydrate and 100 ml of ethanol was heated to reflux for 5 hours. Thesolvent was evaporated under reduced pressure and the residue waspartitioned between methylene chloride and aqueous sodium bicarbonatesolution. The organic phase was dried and evaporated. Crystallizationfrom ether/2-propanol gave end product which was purified bychromatography over 30 g of silica gel using 5% (v/v) of ethanol inmethylene chloride. The analytical sample was recrystallized from ethylacetate/hexane to give light yellow crystals with mp 161°-162° C.

The dihydrochloride of this compound was prepared by heating a solutionin ethanol with excess ethanolic hydrogen chloride and crystallizing byaddition of ether. The analytical sample was recrystallized fromethanol/ether and had mp 178°-182° C. dec.

EXAMPLE 248-Chloro-3-dimethylamino-6-(2-fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine5-oxide

A mixture of 3.8 g (0.01 mole) of7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-4-oxide-2-N'-hydroxy-N,N-dimethylcarboximidamide,1 g (0.033 mole) of paraformaldehyde, 0.3 g of p-toluene sulfonic acidhydrate and 150 ml of ethanol was heated to reflux for 20 hours. Thesolvent was evaporated under reduced pressure and the residue waspartitioned between methylene chloride and sodium bicarbonate solution.The organic layer was dried and evaporated. Crystallization of theresidue from ether/2-propanol gave end product as yellow crystals. Theanalytical sample was purified by chromatography over silica gel using5% (v/v) of ethanol in methylene chloride and crystallized from ethylacetate/hexane to give yellow crystals with mp 203°-206° C.

EXAMPLE 258-Chloro-6-(2-fluorophenyl)-3-pyrrolidinyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A mixture of 1 g of8-chloro-6-(2-fluorophenyl)-3-pyrolidinyl-4H-imidazo[1,5-a][1,4]benzodiazepine5-oxide, 5 g of Raney nickel, 25 ml of tetrahydrofuran and 25 ml ofethanol was hydrogenated at atmospheric pressure for 15 hours. Thecatalyst was removed by filtration over Celite and the filtrate wasevaporated. The residue was passed over silica gel using 5% (v/v) ofethanol in methylene chloride. Crystallization from ether/hexane gaveend product as yellowish crystals with mp 114°-118° C.

EXAMPLE 268-Chloro-6-(2-fluorophenyl)-3-pyrolidinyl-4H-imidazo[1,5-a][1,4]benzodiazepine5-oxide

A mixture of 0.8 g (2 mmole) of7-chloro-5-(2-fluorophenyl)-2,3-dihydro-N-hydroxy-α-(1-pyrrolidinyl)-1H-1,4-benzodazepine-2-methanimine4-oxide, of 0.2 g of paraformaldehyde, 60 mg of p-toluene sulfonic acidand 25 ml of ethanol was heated to reflux for 8 hrs. The reactionmixture was worked up as described above and the residue wascrystallized from ether and a small amount of 2-propanol to give endproduct. It was recrystallized from tetrahydrofuran/2-propanol foranalysis to give light yellow crystals with mp 190°-192° C.

EXAMPLE 278-Chloro-6-(2-fluorophenyl)-3-morpholino-4H-imidazo[1,5-a][1,4]benzodiazepine5-oxide

A mixture of 3 g (7.1 mmole) of7-chloro-5-(2-fluorophenyl)-2,3-dihydro-N-hydroxy-α-(4-morpholinyl)-1H-1,4-benzodiazepine-2-methanimine4-oxide, 0.6 g (20 mmole) of paraformaldehyde, 100 ml of ethanol and 250mg of paratoluene sulfonic acid hydrate was heated to reflux for 16hours. The crude product obtained after the usual workup waschromatographed over 60 g of silica gel using 5% (v/v) of ethanol inmethylene chloride for elution. The clean fractions of product werecombined and evaporated. The residue was crystallized from ether andrecrystallized from ethyl acetate/hexane for analysis to yield endproduct as yellow crystals with mp 200°-203° C.

EXAMPLE 288-Chloro-6-(2-fluorophenyl)-1-methyl-3-morpholino-4H-imidazo[1,5-a][1,4]benzodiazepine

(A) A mixture of 1 g of8-chloro-6-(2-fluorophenyl)-1-methyl-3-morpholino-4H-imidazo[1,5-a][1,4]benzodiazepine5-oxide, 25 ml of tetrahydrofuran, 25 ml of ethanol and ca. 5 g of Raneynickel was stirred under an atmosphere of hydrogen for 15 hours. Thecatalyst was filtered off and the filtrate was evaporated. The residuewas passed over a pad of silica gel using 5% (v/v) of ethanol inmethylene chloride for elution. The eluates were evaporated andcrystallized from ether/hexane to give end product as light yellowcrystals with mp 173°-175° C. The analytical sample was recrystallizedfrom ethyl acetate/hexane, mp 175°-177° C.

(B) A mixture of 0.4 g of7-chloro-5-(2-fluorophenyl)-2,3-dihydro-N-hydroxy-α-(4-morpholinyl)-1H-1,4-benzodiazepine-2-methanimine,5 ml of glacial acetic acid and 0.4 ml of acetaldehyde was heated toreflux for 5 minutes. The usual workup and chromatography of the crudereaction mixture on 5 g of silica gel using 5% (v/v) of ethanol inmethylene chloride gave yellow crystalline product identical with thatdescribed above.

EXAMPLE 298-Chloro-6-(2-fluorophenyl)-1-methyl-3-morpholino-4H-imidazo[1,5-a][1,4]benzodiazepine5-oxide

A mixture of 4.2 g (0.01 mole) of7-chloro-5-(2-fluorophenyl)-2,3-dihydro-N-hydroxy-α-(4-morpholinyl)-1H-1,4-benzodiazepine-2-methanimine4-oxide, 50 ml of glacial acetic acid and 4 ml of acetaldehyde washeated to reflux for 5 minutes. The cooled reaction mixture was pouredon ice, made alkaline with ammonia and extracted with methylenechloride. The extracts were dried and evaporated and the residue wascrystallized from ether/2-propanol to yield yellow crystals.

For analysis the product was purified by passing over silica gel using5% (v/v) of ethanol in methylene chloride and crystallized from ethylacetate, mp 217°-220° C. dec.

EXAMPLE 308-Chloro-6-(2-fluorophenyl)-3-(4-methylpiperazinyl)-4H-imidazo[1,5-a][1,4]benzodiazepine5-oxide

A mixture of 4.3 g (0.01 mole) of7-chloro-5-(2-fluorophenyl)-4-oxide-3H-1,4-benzodiazepin-2-yl](4-methyl-1-piperazinyl)methanoneoxime, 200 ml of ethanol, 100 ml of tetrahydrofuran and 1.6 g of sodiumborohydride was stirred at room temperature for 4 hours. The solventswere evaporated partially under reduced pressure and the residue waspartitioned between methylene chloride and sodium bicarbonate solution.The organic phase was dried and evaporated. The crude product wasconverted to the hydrochloride by treatment with ethanolic hydrogenchloride to give yellow crystals. These crystals were reconverted to thebase by partitioning between methylene chloride and sodium carbonatesolution. The methylene chloride layer was dried and evaporated to leaveresinous7-chloro-5-(2-fluorophenyl)-2,3-dihydro-N-hydroxy-α-(4-morpholinyl)-1H-1,4-benzodiazepine-2-methanimine4-oxide. This material was combined with 125 ml of ethanol, 0.8 g ofparaformaldehyde and 0.4 g of para-toluene sulfonic acid hydrate. Thismixture was heated to reflux for 48 hours and was then evaporated. Theresidue was partitioned between methylene chloride and sodium carbonatesolution. The organic layer was dried and evaporated. Crystallization ofthe dark residue from ether containing a small amount of 2-propanolyielded end product as yellow crystals. For analysis a sample waspurified by passing over silica gel using methylene chloride/methanol1:1 (v/v) and by crystallizing from ethyl acetate/ether to give lightyellow crystals with mp 184°-186° C.

EXAMPLE 317-Chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine

Sodium nitrite, 5 g (0.072 mole), was added in portions over a period of5 min to a solution of 20 g (0.06 mole) of7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine*in 100 ml of glacial acetic acid. Following the addition, the reactionmixture was stirred at room temperature for 15 min. The product, whichcrystallized partially during this period, was further precipitated byslow addition of 50 ml of water and collected by filtration. Thecrystals were washed with water, sucked dry and washed withmethanol/ether to leave light yellow product. The filtrate was dilutedwith water and extracted with methylene chloride. The extracts werewashed with water, dried and evaporated. Crystallization of the residuefrom methylene chloride/hexane yielded additional product. Theanalytical sample was recrystallized from ether to give pale yellowcrystals with mp 220°-230° C. dec.

EXAMPLE 32 7-Chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine 4-oxide

7-Chloro-5-(2-fluorophenyl)-1,3-dihydro-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide*7 g (0.02 mole), was dissolved by heating in 250 ml of glacial aceticacid. The solution was cooled with tap water and when the temperaturereached 70° C. the addition of 1.9 g (0.0275 mole) of sodium nitrite wasstarted. The sodium nitrite was added over a period of 10 min whilecooling was continued. Following the addition, the mixture was stirredfor 11/2 hr at room temperature, diluted with water and extracted withmethylene chloride. The extracts were washed with water, dried oversodium sulfate and evaporated. Crystallization of the residue from ethylacetate yielded yellow crystals.

EXAMPLE 337-Chloro-5-(2-fluorophenyl)-N-methoxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine4-oxide

A solution of diazomethane in ether was added to a suspension of 3.8 g(0.01 mol) of7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine4-oxide in 200 ml of methylene chloride. The mixture was stirred for 1hr at room temperature whereby a clear solution resulted. The excessdiazomethane was destroyed by addition of acetic acid. The reactionmixture was washed with aqueous sodium bicarbonate solution, dried oversodium sulfate and evaporated. Crystallization of the residue from etheryielded yellow crystals. The analytical sample was recrystallized fromether, mp 207°-209°.

EXAMPLE 347-Chloro-5-(2-fluorophenyl)-2-{[4-methoxyimino)methyl]morpholinyl}-3H-1,4-benzodiazepine4-oxide

A mixture of 3.9 g (0.01 mol) of7-chloro-5-(2-fluorophenyl)-N-methoxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine4-oxide, 100 ml of tetrahydrofuran and 5 ml of morpholine was allowed tostand at room temperature for 2 hrs. After partial evaporation underreduced pressure, the reaction mixture was partitioned between methylenechloride and aqueous sodium bicarbonate solution. The organic phase wasdried and evaporated and the residue was crystallized from ether/hexaneto yield yellow crystals with mp 170°-173° C. The analytical sample wasrecrystallized from the same solvents.

EXAMPLE 358-Chloro-6-(2-fluorophenyl)1-methyl-3-morpholino-4H-imidazo[1,5-a][1,4]benzodiazepine5-oxide

A mixture of 215 mg of7-chloro-5-(2-fluorophenyl)-2-{[4,-(methoxyimino)methyl]morpholinyl}-3H-1,4-benzoidazepine4-oxide, 5 ml of ethanol, 5 ml of tetrahydrofuran and 0.2 g sodiumborohydride was stirred at room temperature for 4 hrs. Afterpartitioning between methylene chloride and aqueous sodium bicarbonatesolution, the organic layer was dried and evaporated to leave crude8-chloro-6-(2-fluorophenyl)-2,3-dihydro-2-[4-(methoxyimino)methyl]morpholinyl-1H-1,4-benzodiazepine4-oxide which was dissolved in 5 ml of glacial acetic acid. Followingthe addition of 0.2 ml of acetaldehyde, the solution was heated toreflux for 2 min. Then it was poured on ice, made alkaline with ammoniaand extracted with methylene chloride/ether. The organic layer was driedand evaporated. Crystallization of the residue from ethyl acetate gaveend product with mp 217°-220° C. dec.

EXAMPLE 368-Chloro-6-(2-fluorophenyl)-1-methyl-3-morpholino-4H-imidazo[1,5-a][1,4]benzodiazepine

A mixture of 0.2 g of8-chloro-6-(2-fluorophenyl)-1-methyl-3-morpholino-4H-imidazo[1,5-a][1,4]-benzodiazepine5-oxide, 0.2 ml of hexachlorodisilane and 10 ml of methylene chloridewas allowed to sit for two days. It was then diluted with toluene andwashed with 1 N sodium hydroxide solution. The organic phase was driedand evaporated. Crystallization of the residue from ether/hexane gaveend product with mp 172°-174° C.

EXAMPLE 377-Chloro-5-(2-fluorophenyl)-2-[4-(methoxyimino)methyl]-morpholinyl-3H-1,4-benzodiazepine

Morpholine, 1 ml, was added to a solution of 0.5 g of7-chloro-5-(2-fluorophenyl)-N-methoxy-α-nitro-3H-1,4-benzodiazepine-2-methaniminein 10 ml of tetrahydrofuran. After standing at room temperature for 3hrs, the solvent was evaporated and the residue was partitioned betweenmethylene chloride and aqueous sodium bicarbonate solution. The organiclayer was dried and evaporated. Crystallization of the residue fromether/hexane yielded end product with mp 141°-143° C.

EXAMPLE 387-Chloro-5-(2-fluorophenyl)-2,3-dihydro-2-{[(methoxyimino)methyl]aziridinyl}-1H-1,4-benzodiazepine4-oxide

A mixture of 2 g of7-chloro-5-(2-fluorophenyl)-N-methoxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine4-oxide, 30 ml of tetrahydrofuran and 2 ml of aziridine was allowed tostand at room temperature for 1 hr. After partitioning between methylenechloride and aqueous sodium bicarbonate solution, the organic phase wasdried and evaporated to leave crude7-chloro-5-(2-fluorophenyl)-2-{[(methoxyimino)methyl]aziridinyl}-3H-1,4-benzodiazepine4-oxide.

This material was dissolved in a mixture of 30 ml of ethanol and 30 mlof tetrahydrofuran. After addition of 1 g of sodium borohydride, thesolution was stirred for 4 hrs at room temperature and partitionedbetween methylene chloride and water. The organic layer was dried andevaporated. Crystallization of the residue from ether gave yellowishcrystals with mp 161°-164° C. The analytical sample was recrystallizedfrom ethyl acetate/hexane.

What is claimed:
 1. A compound of the formula ##STR4## wherein X isselected from the group consisting of hydrogen, halogen, nitro andtrifluoromethyl and Y is selected from the group consisting of hydrogen,halogen and trifluoromethyl, R₄ is hydrogen or lower alkyl and R₃ isselected from the group consisting of an amino or substituted amino.